This invention is in the field of antiinflammatory pharmaceutical agents and specifically relates to a crystalline form of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide, methods of preparing the crystalline form, pharmaceutical compositions and methods for treating cyclooxygenase-2 (COX-2) associated disorders, including inflammation.
Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG2, PGH2 and PGE2, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named xe2x80x9ccyclooxygenase-2 (COX-2)xe2x80x9d or xe2x80x9cprostaglandin G/H synthase IIxe2x80x9d) provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects related to inhibition of cyclooxygenase-1 (COX-1).
A group of substituted isoxazoles are described in U.S. Pat. No. 5,633,272, to Talley et al., and International Application WO96/25405. The compounds are described to be useful for the treatment of inflammation and inflammation-associated disorders. 4-[5-Methyl-3-phenylisoxazol-4-yl]benzenesulfonamide shows potential as a selective inhibitor of COX-2 over COX-1.
With all pharmaceutical compounds and compositions, the chemical and physical stability of a drug compound is important in the commercial development of that drug substance. Such stability includes the stability at ambient conditions, especially to moisture and under storage conditions. Elevated stability at different conditions of storage is needed to anticipate the different possible storage conditions during the lifetime of a commercial product. A stable drug avoids the use of special storage conditions as well as frequent inventory replacement. A drug compound must also be stable during the manufacturing process which often requires milling of the drug to achieve drug material with uniform particle size and surface area. Unstable materials often undergo polymorphic changes. Therefore, any modification of a drug substance which enhances its stability profile provides a meaningful benefit over less stable substances.
It has now been discovered that 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide can be prepared in different crystal forms. An earlier material (Form xe2x80x9cAxe2x80x9d) is unstable after mechanical grinding (milling) and is also thermally unstable. A recently determined crystalline form (Form xe2x80x9cBxe2x80x9d) is described which is more stable and has improved physical properties.